Circadian gene variants in cancer

Figures & data

Figure 1. The mammalian circadian clock. (A) The mammalian circadian clock is comprised of circadian input pathways, such as the light input pathway via the retinohypothalamic tract (RHT), the central clock located in the hypothalamic suprachiasmatic nucleus (SCN), the circadian output pathways including the neuroendocrine and autonomic nervous systems (grey arrows) and peripheral clocks in all tissues studied. (B) A simplified model of the molecular clock. Solid lines show direct regulation of the positive and negative feedback loops by core circadian genes Bmal1, Clock, Ck1δ and ϵ, Cry, Naps2, Per, Rev-erbα and β, as well as Rorα and γ. The dashed lines show indirect regulation of Rev-erbα and β by PER. The molecular clock also targets clock-controlled genes (CCGs) that regulate diverse cellular processes. The first-order CCGs are controlled by the molecular clock directly at the transcriptional level.

Table I. Circadian genes in human diseases.

Clock genes	Cancer types	Other diseases	References
Bmal1	Breast, colorectal, head and neck, ovarian, pancreatic, and prostate cancers, B-cell lymphoma, pleural mesothelioma, ALL, AML, and CML	Aging, hypertension, immune deficiency, mood disorders, neurodegeneration, and T2D	(45, 96–108)
CK1δ/ϵ	Breast, colorectal, ovarian, pancreatic, and prostate cancers	Aging, chronic inflammation, hypertension, insulin resistance, neurodegeneration, and sleep disorders	(102, 120–135)
Clock	Breast, colorectal, lung, ovarian, pancreatic, prostate and skin cancers, B-cell lymphoma, and CLL	Bipolar disorder, hypertension, obesity, neurodegeneration, NAFLD, and T2D	(50, 102–104, 106, 139–144)
Cry1/2	Breast, colorectal, endometrial, head and neck, ovarian, pancreatic, prostate and skin cancers, glioma, pleural mesothelioma, CLL, CML, HCC, and NHL	Acute inflammation, hyperglycemia, mood disorders, obesity, Parkinson's, and T2D	(102–105, 125, 126, 134, 139–140, 153–171)
Dec1/2	Breast, endometrial, gastric, head and neck, lung, pancreatic, and renal cancers, and HCC	Autoimmune disease, chronic inflammation, and sleep disorders	(182–194)
Npas2	Breast and prostate cancers, pleural mesothelioma, glioma, and NHL	Aging, chronic fatigue, chronic inflammation, hypertension, mood disorders, and neurodegeneration	(100, 102, 134, 161, 169, 197–204)
Per1/2/3	Breast, colorectal, endometrial, head and neck, lung, ovarian, pancreatic, prostate, skin and thyroid cancers, B-cell lymphoma, glioma, pleural mesothelioma, AML, CLL, CML, and HCC	Aging, cardiovascular disease, chronic inflammation, insulin resistance, neurodegeneration, obesity, eating, mood and sleep disorders, and T2D	(98, 99, 104, 105, 126, 134, 139, 140, 157, 158, 160, 161, 164, 169, 170, 213, 223, 229, 240)
Rorα/γ	Breast, colorectal, pituitary, prostate, and thyroid cancers	Immune deficiency, insulin resistance, and obesity	(122, 255–264)
Rev-erbα/β	Breast and thyroid cancers and pleural mesothelioma	Autoimmune disease, chronic inflammation, and obesity	(162, 256, 273–280)
βTrCP1/2	Breast, colorectal, gastric, pancreatic, and prostate cancers, and HCC	N/A	(284–289)

ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; CML = chronic myeloid leukemia; HCC = hepatocellular carcinoma; NAFLD = non-alcoholic fatty liver disease; NHL = non-Hodgkin's lymphoma; T2D = type 2 diabetes.

Table II. Circadian gene mutant mouse models.

Genetic model	Mouse strain	Mouse phenotype	References
Bmal1^+/−	C57BL/6J	Premature aging, cancer prone	(19, 65)
Bmal1^−/−	C57BL/6J	Arrhythmic, aggressive aging, hypoglycemia, redox deregulation, immune deficiency cellular senescence, cancer prone, metabolic syndromes, neurological disorders	(19, 23, 65, 111–113, 115, 116)
Bmal1^−/− islets or adipocytes	C57BL/6J × 129 × ICR	Hyperglycemia, hypoinsulinemia, adipocyte hyperplasia, redox deregulation	(115, 116)
Bmal1^−/− keratinocytes	C57BL/6J	Genomic instability, cellular senescence, deregulation of cell proliferation and metabolism, redox deregulation	(25, 65)
CK1δ or CK1ϵ	C57/BL6J	Lengthened period, autoimmune diseases, mammary gland neoplasms	(136–138)
^ClockΔ19/ Δ19	C57BL/6J & C57BL6 × BALB/c	Arrhythmic in constant darkness, metabolic syndromes, obesity, premature aging, NAFLD	(21, 66, 116, 145–152)
Clock^−/−	C57BL/6J	Aging, chronic inflammation	(150)
Clock^−/− cardiomyocytes	FVB/NJ	Cardiac dysfunction, fatty acid dysregulation	(149)
Cry1^−/− or Cry2^−/−	C57BL/6J	Abnormal behavioral rhythm, premature aging, hypertension, chronic inflammation, sleep disorder, cancer prone, metabolic syndromes	(21, 61, 173–175)
Cry1^−/−; Cry2^−/−	C57BL/6J	Arrhythmic, premature aging, chronic inflammation, hypertension, impaired tissue regeneration, sleep disorder, cancer prone, metabolic syndromes	(19, 23, 62, 67, 175–178)
Dec1^−/−; Dec2^−/−	C57BL/6J	Lengthened circadian period	(195, 196)
Npas2^−/−	C57BL/6J × 129Sv	Metabolic syndromes, behavioral abnormalities, sleep disorder	(205–208)
Per1^−/−	C57BL/6J	Immune deficiencies, cancer prone	(242, 243, 252)
Per2^−/− or Per2 ^tm1Brd/tm1Brd	C57BL/6J & C57BL/6J × 129Sv	Arrhythmic inconstant darkness, premature aging, cancer prone, metabolic syndromes, vascular diseases, immune deficiency	(19, 22, 23, 173, 241, 250, 253)
Per2^S662G or Per2^S662D	C57BL/6J	Shortened period, premature aging, deregulation of apoptosis, cancer prone	(24, 27)
Per1−/−; Per2 ^tm1Brd/tm1Brd	C57BL/6-Tyr^c-2J	Arrhythmic, premature aging and neurological disorders, cancer prone, metabolic syndromes, neurological disorder	(19, 242, 243, 251)
Per3−/−	C57BL/6 × 129Sv	Metabolic syndromes, arteriosclerotic disease	(249, 250)
Rorα−/− or Rorγ−/−	C57/BL6J	Premature aging, adipocyte hyperplasia, immune-deficient, neurodegeneration	(265–271)
Rev-Erbα^−/−	C57BL/6J × 129Sv	Metabolic syndromes, immune deficiencies	(272, 281, 282)
Rev-Erbα−/−; Rev-erbβ^−/−	C57BL/6J × 129Sv	Arrhythmic, metabolic syndromes	(272)
βTrCP1^m/m	C57BL/6J	Tissue-specific expression of dominant negative mutants promotes tumor development	(298–300, 302)

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